Background: We present 2 patients with verrucous carcinoma (VC) of the foot, a malignancy of unknown origin. Objective: Molecular studies from the VCs were undertaken to determine the presence, type, and physical state of human papillomavirus (HPV) as well as the expression levels of certain oncogenes and antioncogenes. Methods: Synthetic consensus and type-specific primers were used to determine the HPV type from both VCs via polymerase chain reaction (PCR). Verification of fragments was accomplished by means of specific isotope-labeled oligonucleotide probes. The physical state of HPV DNA was determined by two-dimensional gel electrophoresis. Quantitative oncogene and antioncogene expression studies were performed with the use of reverse transcriptase PCR. Results: HPV type 16 was identified in episomal and integrated forms in both tumors. Expression studies revealed increased messenger RNA levels of c-Ki-ras oncogene and the p53 antioncogene and decreased messenger RNA levels of the Rb antioncogene in both VCs. Conclusion: Episomal and integrated forms of HPV-16 DNA were found in VCs of the foot, along with alterations of c-Ki-ras, p53, and Rb genes. (J Am Acad Dermatol 2001;45:49-55.)